Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue

Hilster, Roderick H.J. de; Sharma, Prashant K.; Jonker, Marnix; White, Eric S.; Gercama, E A; Roobeek, M; Timens, Wim; Harmsen, Martin C.; Hylkema, Machteld N.; Burgess, Janette K.

doi:10.1152/ajplung.00451.2019

Cited by 109 publications

(123 citation statements)

References 30 publications

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“…Tissue fibrosis is a pathological scarring process characterized by the excessive deposition of crosslinked extracellular matrix (ECM) proteins leading to progressive matrix stiffening and decreased viscoelasticity 25,35,48,61,79,82 . These aberrant changes in tissue mechanics detrimentally impact organ function, contributing to the role fibrosis plays in nearly half of all deaths in the developed world 33,52,81 .…”

Section: Introductionmentioning

confidence: 99%

The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation

Hui

Moretti

Barker

et al. 2021

Preprint

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Tissue fibrosis is characterized by progressive extracellular matrix (ECM) stiffening and loss of viscoelasticity that ultimately results in reduced organ functionality. Cells bind to the ECM through integrins, where αv integrin engagement in particular has been correlated with fibroblast activation into contractile myofibroblasts that drive fibrosis progression. There is a significant unmet need for in vitro hydrogel systems that deconstruct the complexity of native tissues to better understand the individual and combined effects of stiffness, viscoelasticity, and integrin engagement on fibroblast behavior. Here, we developed hyaluronic acid hydrogels with independently tunable cell-instructive properties (stiffness, viscoelasticity, ligand presentation) to address this challenge. Hydrogels with mechanics matching normal or fibrotic lung tissue were synthesized using a combination of covalent crosslinks and supramolecular interactions to tune viscoelasticity. Cell adhesion was mediated through incorporation of either RGD peptide or engineered fibronectin fragments promoting preferential integrin engagement via αvβ3 or α5β1. We showed that preferential αvβ3 engagement enabled human lung fibroblasts to assume a myofibroblast-like phenotype on fibrosis-mimicking stiff elastic hydrogels with increased spreading, actin stress fiber organization, and focal adhesion maturation as indicated by paxillin organization. In contrast, preferential α5β1 binding suppressed these metrics. Viscoelasticity, mimicking the mechanics of healthy tissue, largely curtailed fibroblast spreading and focal adhesion organization independent of adhesive ligand type, highlighting its role in preventing fibroblast activation. Together these results provide new insights into how mechanical and adhesive cues collectively guide disease-relevant cell behaviors.

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Section: Introductionmentioning

confidence: 99%

The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation

Hui

Moretti

Barker

et al. 2021

Preprint

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“…Collagen has a prominent role in the pathogenesis of disease; deposits in the alveolar walls progressively destroy normal alveolar architecture [ 87 , 88 ]. From a mechanical perspective, decellularized and native IPF samples displayed higher stiffness than healthy lung samples [ 57 , 89 ]. The Young’s moduli derived from AFM and a low-load compression testing are listed in Table 3 .…”

Section: The Role Of Collagen In Airway Disease and Disease-associmentioning

confidence: 99%

“…Average IPF tissue stiffness (18.9 ± 11.1 kPa) was higher than healthy control (3.7 ± 1.3 kPa); Stiffness of hydrogel derived from IPF tissue (6.8 ± 2.8 kPa) was greater than hydrogel from healthy control (1.1 ± 0.2 kPa), as detected by a low-load compression tester [ 89 ].…”

Section: The Role Of Collagen In Airway Disease and Disease-associmentioning

confidence: 99%

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Role of Collagen in Airway Mechanics

et al. 2021

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Collagen is the most abundant airway extracellular matrix component and is the primary determinant of mechanical airway properties. Abnormal airway collagen deposition is associated with the pathogenesis and progression of airway disease. Thus, understanding how collagen affects healthy airway tissue mechanics is essential. The impact of abnormal collagen deposition and tissue stiffness has been an area of interest in pulmonary diseases such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In this review, we discuss (1) the role of collagen in airway mechanics, (2) macro- and micro-scale approaches to quantify airway mechanics, and (3) pathologic changes associated with collagen deposition in airway diseases. These studies provide important insights into the role of collagen in airway mechanics. We summarize their achievements and seek to provide biomechanical clues for targeted therapies and regenerative medicine to treat airway pathology and address airway defects.

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“…During the progression of many chronic respiratory diseases, considerable changes to the mechanical properties of the lung tissue have been characterized (66). In fibrotic diseases such as idiopathic pulmonary fibrosis and pulmonary arterial hypertension, an aberrant healing response and excess collagen deposition lead to increases in lung stiffness from 1-5 kPa (healthy) to over 10 kPa (fibrotic) (84,85), while COPD results in an overall decrease in tissue organization and stiffness (85). Biomaterials mimicking these dynamic changes in extracellular matrix mechanics could be readily designed to provide sophisticated in vitro models of patient-specific disease and treatment (80,86).…”

Section: Opportunities For Tissue-informed Biomaterials To Advance Pulmonary Regenerative Medicinementioning

confidence: 99%

Engineering Tissue-Informed Biomaterials to Advance Pulmonary Regenerative Medicine

et al. 2021

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Biomaterials intentionally designed to support the expansion, differentiation, and three-dimensional (3D) culture of induced-pluripotent stem cells (iPSCs) may pave the way to cell-based therapies for chronic respiratory diseases. These conditions are endured by millions of people worldwide and represent a significant cause of morbidity and mortality. Currently, there are no effective treatments for the majority of advanced lung diseases and lung transplantation remains the only hope for many chronically ill patients. Key opinion leaders speculate that the novel coronavirus, COVID-19, may lead to long-term lung damage, further exacerbating the need for regenerative therapies. New strategies for regenerative cell-based therapies harness the differentiation capability of human iPSCs for studying pulmonary disease pathogenesis and treatment. Excitingly, biomaterials are a cell culture platform that can be precisely designed to direct stem cell differentiation. Here, we present a closer look at the state-of-the-art of iPSC differentiation for pulmonary engineering, offer evidence supporting the power of biomaterials to improve stem cell differentiation, and discuss our perspective on the potential for tissue-informed biomaterials to transform pulmonary regenerative medicine.

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Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue

Cited by 109 publications

References 30 publications

The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation

The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation

Role of Collagen in Airway Mechanics

Engineering Tissue-Informed Biomaterials to Advance Pulmonary Regenerative Medicine

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